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Introduction to Pharmaceuticals and Personal Care Products (PPCPs) Christian G. Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory Office of Research and Development Environmental Protection Agency Las Vegas, Nevada 89119 [email protected] U.S. EPA Notice Although this work was reviewed by the U.S. Environmental Protection Agency (EPA) and approved for presentation, it may not necessarily reflect official Agency policy. While the text for this . presentation has been reviewed, the oral narrative has not. Mention of trade names or commercial products does not necessarily constitute endorsement or .. recommendation by EPA for use. Wealth of other materials and links to most of the ongoing work relevant to this topic are available at the U.S. EPA’s PPCPs Web Site: http://www.epa.gov/nerlesd1/chemistry/pharma Historical Perspective - PPCPs PPCPs as environmental pollutants first investigated in Europe 1980s. With the advent of monitoring and research in the U.S., literature has grown exponentially since 2000. PPCPs are not truly "emerging" pollutants. It is the understanding of the significance of their occurrence in the environment that is beginning to develop. Topic has high public visibility. Continues to attract significant media attention - newspapers, magazines (popular, trade, and science), radio, and TV. Overall issue comprises numerous facets involving expertise from a broad spectrum of disciplines ranging from human health to ecology - - necessitating communication between the medical/healthcare communities and environmental scientists. Sampling of Organizations Involved with PPCP Activities USGS: Emerging contaminants national reconnaissance in nation's water resources CDC: CAFOs, with focus on antibiotics and steroids FDA: FONSIs or EAs for all new drugs (EIC of 1 ppb is the determining factor) USDA: CAFOs, with focus on antibiotics and steroids U.S. Grants: U.S. EPA STAR, USGS/Water Resources Research Institute, AwwaRF, WateReuse Foundation, Sea Grants other GOs: Health Canada, EMEA (European Medicines Agency), Danish EPA Researchers: Academic, private (engineering consulting), and public (e.g., water providers) in Europe, Scandinavia, Canada, and U.S. PhRMA: Pharmaceuticals Research and Manufacturers of America – PIE Task Force Health Care Community: esp. hospital wastes State and Local Governments: expanding interest in “take-back” programs; groundwater recharge monitoring Some Significant Current Projects on Pharmaceuticals SETAC Pharmaceuticals Workgroup (formed at the Portland meeting in Fall 2004 by Dr. Hans Sanderson, Soap and Detergent Association, Washington, DC: [email protected]). Comprises subcommittees on: Environmental Effects; Chemical Fate & Predicted Environmental Concentrations; Water Treatment & Management; Environmental Risk Assessment; Future Criteria for Risk Management; Mixtures. Product Stewardship Institute (PSI), Inc. Project on Pharmaceutical Wastes (begun in May 2005) focusing primarily on unwanted or waste pharmaceutical products from households. Scott Cassel, Executive Director, Boston, MA: [email protected] Federal Interagency Task Group on PPCPs. Created in September 2004 by the National Science and Technology Council's subcommittee on Health and the Environment. Chaired by the U.S. FDA and comprises representatives from the CDC, NIEHS, USGS, USDA, FDA, NOAA, and EPA. A major objective is to recommend how the various federal agencies having roles related to pharmaceuticals as environmental pollutants can prioritize research, better coordinate their efforts, and collaborate more effectively. An EPA contact is Christian Daughton: [email protected] Scope of Issue Thousands of distinct chemical entities. Numerous (and increasing) therapeutic classes and end uses. Large numbers possess very high biological activity. Two classes of therapeutics that have received the most attention are the antibiotics (potential for resistance selection among pathogens) and steroidal hormones (overlap with EDCs). For the plethora of other classes, however, little is known regarding the potential for effects. In general, PPCPs are not regulated water pollutants. Regulated pollutants compose but a very small piece of the universe of chemical stressors to which organisms can be exposed on a continual basis. PPCPs as Environmental Pollutants? PPCPs are a diverse group of chemicals comprising all human and veterinary drugs (available by prescription or over-the-counter; including the new genre of “biologics”), diagnostic agents (e.g., X-ray contrast media), “nutraceuticals” (bioactive food supplements such as huperzine A), and other consumer chemicals, such as fragrances (e.g., musks) and sun-screen agents (e.g., methylbenzylidene camphor); also included are “excipients” (so-called “inert” ingredients used in PPCP manufacturing and formulation). Clarification of Acronyms Pharmaceuticals & Personal Care Products: “PPCPs” Endocrine Disrupting Compounds: “EDCs”† †A plethora of other terms have often been used interchangeably with EDCs (rightly and wrongly). These include: environmental estrogens, endocrine-disruptors, endocrine-modulators, estrogenic mimics, ecoestrogens, environmental hormones, xenoestrogens, hormonerelated toxicants, hormonally active agents (HAAs), endocrine-active chemicals (EACs), endocrine active substances (EASs), phytoestrogens (a naturally occurring subset). [Note: estrogens account for but one mode of action – others include androgens and thyroid hormones] Groupings of Chemical Pollutants: Confusion from Their Intersections and Acronyms Grouping EDC (Endocrine Disrupting Chemical) CMR (Carcinogenic, Mutagenic, toxic to Reproduction) Grouped According to: toxicological mode of action or endpoint PBT (Persistent, Bioaccumulative Toxic) environmental properties vPvB (very Persistent, very Bioaccumulative) POP (Persistent Organic Pollutant) PPCPs type of intended usage priority pollutants and others legislation “emerging” contaminants/pollutants Novelty, fad, timeliness, or new concern EDCs vs. PPCPs PPCPs EDCs PPCPs and EDCs are not synonymous — they are intersecting sets of large, diverse chemical galaxies. Must avoid confusion regarding their relationship. Only a small subset of PPCPs are known/suspected of being direct-acting EDCs (e.g., synthetic steroids); toxicological concerns usually differ for every therapeutic class. EDCs comprise members from many disparate chemical classes other than PPCPs. Hormones & EDCs A more recent definition of a “hormone” (by Nobel Laureate Roger Guillemin) suggests a much broader definition: "Any substance released by a cell which acts on another cell, near or far..." Hormones are produced in many sites throughout the body and may be released directly into the blood, into neuronal synapses, or into the immediate intercellular space to affect adjacent cellular activity. Attempts to focus attention on chemicals that can “disrupt” or “modulate” endocrine pathways must be sure to sufficiently narrow the scope of concern — otherwise the terminology becomes so broad as to lose meaning. The ultimate objective of all these signaling molecules (chemical messengers) is to maintain cellular, organ, and organism HOMEOSTASIS and to control physiological processes. Endocrine Modulators and Homeostasis Hormones: secreted from endocrine sources and some neurons; transported by blood to remote targets (nuclear receptors). Regulate gene transcription (e.g., sex steroids). Slow-acting. continuum biochemical agents for maintaining cellular, organ, and organism HOMEOSTASIS and controlling physiological processes Pheromones: secreted by exocrine glands; targets outside body; integrate social activities between animals. Endocrine Physiology Neurotransmitters: secreted from neurons and act on immediately adjacent target cells for a short time (e.g., acetylcholine). Local signaling molecules: secreted from cells of many different tissues; act locally; quickly degraded. Neuroendocrinology Neurophysiology C.D. Daughton, 21 November 2001 U.S. EPA-Las Vegas EDCs versus PPCPs Hormones: secreted from endocrine sources and some neurons; transported by blood to remote targets (nuclear receptors). Regulate gene transcription (e.g., sex steroids). Slow-acting. continuum biochemical agents for maintaining cellular, organ, and organism HOMEOSTASIS and controlling physiological processes Pheromones: secreted by exocrine glands; targets outside body; integrate social activities between animals. EDCs Neurotransmitters: secreted from neurons and act on immediately adjacent target cells for a short time (e.g., acetylcholine). Local signaling molecules: secreted from cells of many different tissues; act locally; quickly degraded. preponderance of action PPCPs C.D. Daughton, 21 November 2001 U.S. EPA-Las Vegas Non-Hormonal Endpoints from Hormones Genotoxicity Reactive Intermediates P450 oxidation of estrogens (whether endogenous, synthetic hormones, industrial products, or natural products) Estradiol (E2) P450 o-Quinones forms reactive semiquinone and quinone intermediates. Estrone (E1) If quinones are not quickly removed by COMT (catechol-O-methyltransferase) 2-OH-E2 P450 COMT Inactive Metabolites they bind to DNA and lead to de-purination.and genotoxicity. 16-α-OH-E1 2&4-methoxy-E2 4-OH-E2 "Emerging" Pollutants vs. Emerging Awareness The vast majority of all "emerging" pollutants are not new to the environment Two major sources for pollutants that are truly "new" to the environment: Chemicals newly introduced to commerce (e.g., new drugs or pesticides). New anthropogenic processes (e.g., gallium arsenide quantum dots). Previously unrecognized pollutants can come to our attention as a result of: New advances in chemical analysis (e.g., "non-target" identification). Ability to detect existing pollutants at ever-lower concentrations (e.g., N-nitrosodimethylamine - NDMA). Exploring environmental "compartments" not previously considered (e.g., foods as a significant source of acrylamide). PPCPs as “Emerging” Risks? It is reasonable to surmise that the occurrence of PPCPs in waters is not a new phenomenon. It has only become more widely evident in the last decade because continually improving chemical analysis methodologies have lowered the limits of detection for a wide array of xenobiotics in environmental matrices. There is no reason to believe that PPCPs have not existed in the environment for as long as they have been used commercially. “PBTs” - “POPs” - “BCCs”: Only one part of the risk puzzle? Since the 1970s, the impact of chemical pollution has focused almost exclusively on conventional “priority pollutants”†, especially on those collectively referred to as “persistent, bioaccumulative, toxic” (PBT) pollutants, “persistent organic pollutants” (POPs), or “bioaccumulative chemicals of concern” (BCCs). The “dirty dozen” is a ubiquitous, notorious subset of these, comprising highly halogenated organics (e.g., DDT, PCBs). The conventional priority pollutants, however, are only one piece of the larger risk puzzle. an historical note: the current “lists” of priority pollutants were originally established in the 1970s in large part based on which chemicals of initial concern could be measured with off-the-shelf chemical analysis technology. Priority pollutants were NOT selected because they posed the sole risks. † What portion of overall risk is contributed by unregulated pollutants? Can risk be assessed in a truly holistic manner without knowing the actual exposure universe? The Chemical Universe The KNOWN Universe As of August 2005, over 26 million organic and inorganic substances had been documented. (indexed by the American Chemical Society's Chemical Abstracts Service in their CAS Registry; excluding bio-sequences such as proteins and nucleotides) Of the 26 million known chemicals, nearly 9 million were commercially available. Representing a 12% increase over the prior year. Of these, fewer than a quarter million (240,000) were inventoried or regulated by numerous government bodies worldwide - - representing less than 3% of those that are commercially available or less than 1% of the known universe of chemicals. http://www.epa.gov/nerlesd1/chemistry/pharma/critical.htm The Chemical Universe The POTENTIAL Universe While the KNOWN universe of chemicals might seem large (26 million), the universe of POTENTIAL chemicals (those that could possibly be synthesized and those that already exist but which have not yet been identified) is unimaginably large. How many distinct organic chemical entities could hypothetically be synthesized and added to a seemingly limitless, ever-expanding chemical universe? By limiting synthesis strictly to combinations of 30 atoms of just C, N, O, or S, more than 1060 structures are possible ! Expanding the allowable elements to other heteroatoms (e.g., P and halogens), the limits to the numbers of possible structures defies imagination. Also known as “chemical space”. For more discussion, see: http://epa.gov/nerlesd1/chemistry/pharma/critical.htm Prevalence/Distribution of Xenobiotic Occurrence Prevalence of Xenobiotic Occurrence: Some Possible Generalizations Regarding Ubiquity The lower the concentration, the higher the probability of larger numbers of distinct chemicals occurring Exponentially more types of chemicals occur at exponentially lower concentrations (does the distribution of chemical types versus their concentrations follow a power law, as shown for such a wide array of other phenomenon? e.g., see: M. Buchanan "Ubiquity", Crown Publishers 2000) At the very lowest concentrations (zeptomolar to yoctomolar, zM - yM), the off-the-cuff truism may apply: "Everything can be found everywhere" Einstein on: Environmental Monitoring “Not everything that can be counted counts, and not everything that counts can be counted.“ (oft attributed to Albert Einstein) corollary for environmental monitoring Not everything that can be measured is worth measuring, and not everything worth measuring is measurable. further truisms regarding Environmental Monitoring What one finds usually depends on what one aims to search for. Only those compounds targeted for monitoring have the potential for being identified and quantified. Those compounds not targeted will elude detection. The spectrum of pollutants identified in a sample represent but a portion of those present and they are of unknown overall risk significance. Environmental Exposure Occurs as a result of the combined actions, activities, and behaviors of multitudes of individuals. Inadvertent discharge: Excretion to sewage. Analogous origins occur from veterinary and agriculture usage (e.g., CAFOs). Purposeful discharge: Disposal of expired/unwanted PPCPs to toilets and drains as well as trash. Of the eight “grand challenges” identified in the NRC’s 2000 report (Grand Challenges in Environmental Sciences), one "encompasses questions about societal-level consumption patterns, since consumption is the primary force driving human perturbations of material cycles.” Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdf Inter-Connectedness of Humans and the Environment Occurrence of PPCPs in the environment mirrors the intimate, inseparable, and immediate connection between the actions and activities of individuals and their environment. PPCPs owe their origins in the environment to their worldwide, universal, frequent, and highly dispersed but cumulative usage by multitudes of individuals. Ramifications Exposure at therapeutic doses is NOT the concern. Exposure to non-target organisms could be significant. Continual input via treated sewage imparts PPCPs with "pseudo-persistence" even if they have short half-lives. Aquatic organisms can suffer continual exposure. Potential exists for subtle effects (e.g., neurobehavioral change), even at ppb levels (μg/L). Potential exists for inhibition of aquatic defensive mechanisms such as efflux pumps. Pose many challenges for the outer envelope of toxicology especially the many unknowns associated with effects from simultaneous exposure to multiple chemical stressors over long periods of time. Potential for additive (cumulative) and interactive (synergistic) effects from multiple exposure. Toxicity of Complex Environmental Mixtures: Poses Major Unanswered Questions Exposure to Multiple, Trace-Level Xenobiotics below Known Effects Levels Potential Toxicological Significance as a Result of: (1) Potential for additive effects from multiple agents sharing common mechanisms action (MOAs). Individual concentrations combine to exceed an effects level. (2) Possible interactive effects, especially synergism, where combined action exceeds the sum of individual effects. (3) Hormesis – Effects below purported NOELs. Paradoxical “U-shaped” dose-response curves. continued > Potential Toxicological Significance as a Result of: (4) Dynamic Dose-Response. Toxicant-Induced Loss of Tolerance (TILT): initial exposure sensitizes, and subsequent exposures to levels below those previously tolerated trigger symptoms (e.g., ecological version of MCS). (5) Comparatively little research performed at extremely low concentrations (nM-pM and below). Some agents have ability to impart previously unrecognized effects at "ultra-trace" concentrations. (6) Non-target species receptor repertoires not well characterized. Variation in receptor repertoires across species, and unknown overlap with humans leads to countless questions regarding potential effects. continued > Potential Toxicological Significance as a Result of: (7) Susceptible genetic outliers within species. (8) MOAs not fully understood. Even most drugs can each have a multitude of effects. Most MOAs for the therapeutic endpoints, however, remain to be discovered, even for humans. - concluded - PPCPs in Receiving Waters: A Global, Ubiquitous Process with Unique Local Expression Important to recognize that ALL municipal sewage, regardless of location, will contain PPCPs. Issue is not unique to any particular municipal area. Each geographic area will differ only with respect to the types, quantities, and relative abundances of individual PPCPs. Aquatic organisms — captive to continual, lifecycle chemical exposures Aquatic Exposure is Key: Any chemical introduced via sewage to the aquatic realm can lead to continual, multigenerational exposure for aquatic organisms. Re-evaluation of “Persistence”: Chemicals continually infused to the aquatic environment essentially become “persistent” pollutants even if their half-lives are short — their supply is continually replenished (analogous to a bacterial chemostat). These can be referred to as pseudo-persistent chemicals (P2’s). Bioconcentration: New Paradigm ? Low octanol-water partition coefficients (high polarity) would seem to preclude bioconcentration for most PPCPs. Examples of those subject to bioconcentration include: synthetic musks, sunscreen filters, parabens, triclosan, triclocarban. But certain drugs, despite their low lipid solubilities, are being detected in aquatic tissues in concentrations enriched from those in the ambient water. This is perhaps partly a result of drugs being designed to take advantage of gaining intracellular access via active transport : Examples: estrogens (concentrated in fish bile 60,000 X) gemfibrozil (concentrated in fish tissue, 113 X) diclofenac (concentrated in fish) fluoxetine (concentrated in muscle, liver, and brain of fish) Potential for Subtle Effects? continued > Potential for Subtle (currently unrecognized) Effects? Could immediate biological actions on non-target species be imperceptible but nonetheless lead to adverse impacts as a result of continual accretion over long periods of time? For example, latent damage, only surfacing later in life. The issue of “resiliency”. Could subtle effects accumulate so slowly (perhaps seeming to be part of natural variation) that major outward change cannot be ascribed to the original cause? Effects that are sufficiently subtle that they are undetectable or unnoticed present a challenge to risk assessment (especially ecological) — e.g., subtle shifts in behavior or intelligence. Advances required in developing/implementing new aquatic toxicity tests to better ensure that such effects can be detected. continued > Subtle, Difficult-to-Detect Effects: some examples Profound effects on development, spawning, and wide array of other behaviors in shellfish, ciliates, and other aquatic organisms by SSRI and tricyclic antidepressants (ppb levels). Dramatic inhibition of sperm activity in certain aquatic organisms by calcium-channel blockers. Antiepileptic drugs (e.g., phenytoin, valproate, carbamazepine) have potential as human neuroteratogens, triggering extensive apoptosis in the developing brain neurodegeneration. ppm and sub-ppm levels of various drugs (NSAIDS, glucocorticoids, anti-fibrotics) affect collagen metabolism in teleost fish, leading to defective/blocked fin regeneration Multi-drug transporters (efflux pumps) are common defensive strategies for aquatic biota — possible significance of efflux pump inhibitors in compromising aquatic health? Peeking at the Future Critical Importance of Futuring & Anticipatory Research Important to design and implement a range of mechanisms for providing insight as to those types of pollutants and sources that could emerge in the future. Pollution Prevention and Stewardship programs can be less costly than remediation (Precautionary Principle), pollutant “musical chairs” (pollutant diversion), or “pollution postponement” (storage such as in landfills). continued > The World’s Accessible Freshwater Resources Critical Importance of Forging Better Linkages between Science and the Public continued > Which water would you choose ? Recycled Sewage or Snow Melt ? Key to Maintaining & Improving the Public's Confidence in Water Supplies Growing pressures to re-use wastewaters for drinking "Increasingly Smaller Recycle Loops": Ever-shortening spatial & temporal hydraulic connectivity between point of wastewater discharge and point of use for drinking will pose serious challenges for ensuring human safety and for framing how risk is perceived by the consumer. Two Major Issues: Groundwater Recharge (both indirect and direct) De-Centralized Water Re-Use - - "Toilet-to-tap" WATER RE-USE To Pee or Not to Pee Maybe there's another reason they're called PPCPs? We are what we drink, we drink what we are. Key Role of Beliefs in Public Acceptance of Recycled Water Historically, some water re-use projects have become "branded" with negative images by consumers. Negative images cannot necessarily be erased or corrected by more or even better science. In fact, studies show that additional supportive data often serves to exacerbate already-formed negative images. Instead, we must involve social psychologists to bridge the communications gap between science and the public. The "yuck factor" associated with so-called "toilet-to-tap" programs, for example, derives from beliefs that have long been imbedded in social belief constructs, and these beliefs are refractory to being influenced by positive findings of science. continued > Key Role of Beliefs in Public Acceptance of Recycled Water The principles of logic upon which certain beliefs are based derive from what are known as the "common laws of magic," one of which is the Law of Association, which in turn comprises the sub-laws of Similarity and Contact or Contagion. These “laws” partly originated with the Alchemists, and therefore have a distant relationship with chemistry. The Law of Similarity states that like things produce like things (effects resemble their causes). The Law of Contagion holds that once contaminated, always contaminated. "Things that have once been in contact with each other continue to act on each other at a distance even after physical contact has been severed." Once objects come into contact with each other they will continue to influence each other, even after separation. continued > Risk Communication and Water Re-Use An examination in new light of the problems with communicating risk, especially with regard to groundwater injection and water reuse: Daughton C.G. "Groundwater Recharge and Chemical Contaminants: Challenges in Communicating the Connections and Collisions of Two Disparate Worlds," In Fate and Transport of Pharmaceuticals and Endocrine Disrupting Compounds (EDCs) During Ground Water Recharge (special issue), Ground Water Monitoring & Remediation, 2004, 24(2): 127-138. http://www.epa.gov/nerlesd1/chemistry/ppcp/images/water-reuse.pdf continued > Real-world lesson in communicating: Outhouse Springs Bottled Water Experiment by: Adams Outdoor Advertising, South Carolina, 2002 http://www.outhousesprings.com/index.html concluded Future topics where PPCPs could play major roles Water recycling: With water reuse, especially "toilet-to-tap" programs, the occurrence of even ultra-trace levels of human-use drugs in water serves to highlight to the public what the origin of the water was. This risk-communication/perception problem will pose major problems with regard to public acceptance. Biosolids: The occurrence and fate of PPCPs in biosolids was unknown (NRC July 2002 report: Biosolids Applied to Land: Advancing Standards and Practices). Biopharming: Environmental ramifications of molecular farming or "biopharming" (plant-made pharmaceuticals) are unknown. Nanomaterials: The environmental fate and ramifications of nanomaterials (which will play ever-growing roles in nanomedicine) are unknown. Homeland Security: Certain PPCPs hold the potential for being used in water sabotage (e.g., psychoactive agents; teratogens). Early-Warning Water Monitoring Unregulated (including "emerging") pollutants could provide critical missing pieces for the larger holistic risk puzzle. Designing and implementing early-warning watermonitoring systems could prove essential for providing a better understanding of the larger risk universe. Low-cost, rapid monitoring is theoretically possible for non-target pollutants with the use of analytical approaches based on "change detection" - - using changes in pollution "fingerprints" to focus solely on those unknown contaminants that are newly present. This is in distinct contrast with traditional target-based monitoring. continued > Early-Warning Water Monitoring Early-warning, change-based water monitoring could also prove essential for assisting with five other critical issues facing society. (1) Homeland Security - - Minimizing chances of widespread exposure resulting from sabotage of water systems. (2) Water Re-use/Recycling - - Solidifying & maintaining public trust in water supplies (critical for attaining public acceptance of water reuse). (3) Detecting unanticipated impacts of technology on the environment - impacts can go undetected until a pollutant establishes a widespread presence in the environment. (4) Enhanced science literacy (changing consumer behavior & perceiving of risk) - - improved public understanding that chemicals derived from consumer actions and activities can gain immediate access to the environment (5) Advanced warning of new trends in drugs of abuse - - Previously unknown trends in usage of drugs of abuse (increases and reductions) can theoretically be revealed by monitoring sewage. - concluded - Risk Communication and Water Re-Use Society's perplexing relationship with the paradoxical simplicity and complexity of water is reflected perhaps in no better way than by DH Lawrence's The Third Thing (Pansies 1929): Water is H20 Hydrogen two parts Oxygen one But there is a third thing That makes it water. And nobody knows what that is. Questions feel free to contact: Christian Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory U.S. Environmental Protection Agency [email protected] 702-798-2207 http://www.epa.gov/nerlesd1/chemistry/pharma/ prepared for: Non-Regulated Pollutants Workshop: Brominated Flame Retardants (BFRs) and Pharmaceuticals & Personal Care Products (PPCPs) Pollutants of Emerging Concern Panel Series U.S. EPA Region 2 New York, NY 26 October 2005 Christian Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory U.S. Environmental Protection Agency [email protected] 702-798-2207 prepared: 7 October 2005